Immunotherapy: Who’s Who in the Immune System

(PART TWO OF THREE)

Making sense of some very complicated stuff only a few scientists truly understand: A guide to the immune system for the rest of us.

Let’s think of the immune system as a Broadway musical. The star of the show is the T cell (actually, there are a bunch of different types of T cells, but let’s just focus on the Killer T cell, not to be confused with the “natural killer” cell; see below).

Killer T cells: These cells live up to their name: they’re precision assassins. When they are on their “A game,” they are merciless, and nothing, not even cancer, stands a chance. “They’re my personal favorite cell in the world,” says immunotherapy expert Chuck Drake, M.D., Ph.D. “They’re incredible. They can go anywhere, and kill any other cell if it has the right target,” or flag.

“T cells are amazing,” agrees medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. “They can move out of the bloodstream and go in the bone marrow, the lungs, the liver, and start attacking cancer wherever it is. They have little sensors on their surface that can recognize viruses you haven’t even been affected with yet – just because they’re foreign.”

However: Cancer knows how to snake-charm these cells, to put them into a trance, or a straitjacket, or to put the “boot” on their tires so they can’t go anywhere – pick your metaphor, but the bottom line is that cancer temporarily takes the T cells out of commission. Cancer cells have ways to put T cells to sleep – but not kill them – on a large scale. If you’re a James Bond fan, think of that scene in “Goldfinger,” when planes fly over Fort Knox and cropdust entire platoons – soldiers with loaded guns at the ready – with gas that makes them drop instantly. Or that moment in “Sleeping Beauty” when the entire kingdom plunges into a 100-year slumber, waiting for the handsome prince to come save the day. One of prostate cancer’s first official functions is to deactivate the T cells with molecules that act as brakes, or checkpoints.

Checkpoint inhibitors are like the handsome prince: they allow the kingdom of T cells to wake up. There are several checkpoints, or sleeping potions. One is PD-1. Another is CTLA-4. In their proper role, checkpoints are good. “Nature doesn’t want a T cell to kill off your kidney or gastrointestinal tract,” says Simons. In an autoimmune disease, for instance, T cells are misdirected; they mistake good and decent cells for the enemy, and destroy tissue. When someone gets an organ transplant, unless the immune system is suppressed, the body will reject the foreign organ. “The reason transplants are rejected is that T cells realize that these cells are foreign, and within days or even hours destroy every last one.” Thus, the body’s checkpoints. “Nature is very sophisticated about keeping T cells from going crazy. T cells that make a mistake can be fatal.”

But cancers that successfully keep T cells from doing their job can be fatal, too, and cancer cells co-opt checkpoints so successfully that there can be a T cell sitting right next to a cancer cell and the T cell does nothing, because the cancer is sending a signal saying, “I’m normal, don’t kill me.”

Checkpoints such as PD-1 are tiny molecules sitting on individual T cells. And incredibly, there are several drugs that can deactivate them. Pembrolizumab and Nivolumab target PD-1. A drug called ipilimumab targets CTLA-4. For each checkpoint – and it’s still not clear exactly how many there are – potentially, there is some way to block it, and the Prostate Cancer Foundation is actively funding this research.

From what we know right now, it seems that a minority of men with prostate cancer respond to PD-1 blocking drugs. Only a few men with prostate cancer respond to ipilimumab. Scientists aren’t sure why. But maybe the men with prostate cancer who don’t respond to those drugs will respond to different checkpoint inhibitors.

A new and promising checkpoint to target for cancer immunotherapy is Vista. “Vista may be a major switch” that really puts T cells to sleep, Simons explains. If checkpoints like PD-1 put a T cell into a trance, Vista might put it into a deep sleep – think of Juliet faking her own death in Shakespeare’s play, sleeping so deeply that her heart barely pumped and her lungs barely breathed. When cancers make Vista, T cells are exceptionally sleepy. A drug that blocks Vista might make those cells be exceptionally wide awake. An anti-Vista drug “just went into clinical trials for prostate cancer.” It might take a cocktail of antidotes – anti-PD-1, anti CTLA4, anti-Vista – to allow T cells to achieve maximum killing potential against prostate cancer.

IDO: Indolamine amase (IDO) is the reason your mother’s body didn’t reject you in the womb. It’s a gene made in the placenta. Cancer cells stole the recipe; they make it, too, to keep your body from rejecting them.

Now, back to that Broadway musical: There don’t seem to be any bit players in the immune system. Yes, T cells are the stars, but there are plenty of potential stars waiting in the wings. These include:

Natural Killers. These sound like something Quintin Tarentino would write about, but really, they’re foot soldiers that work with the T cells to fully execute on an enemy. Natural killer cells are really good at killing and they can do it quickly, without the education that T cells require, meaning they can get to the battle site first and start the battle. However, they also lack the specificity that T cells have, as well as the proliferation capacity and life-long lifespan. T cells are needed for precision execution and to perform ongoing life-long surveillance for any rogue tumor cells that went into hiding. Checkpoint inhibitors aimed at helping unleash natural killer cells are being developed.

Macrophages. When cancer cells die, there’s carnage. Macrophages are early responders to the crime scene, and they chew up the debris. GM-CSF activates macrophages. Physician-scientist and PCF-funded investigator Padmanee Sharma, M.D., Ph.D., of MD Anderson Cancer Center, suspects that some types of prostate cancer may be more susceptible to immunotherapy drugs that activate the macrophages, rather than, or in addition to, the T cells. But macrophages aren’t just scavengers. “They do something very important: they educate T cells to recognize cancer cell flags,” explains Simons, “so they’re like educator garbage men.” T cells need macrophages to show them the ropes – so they can find the flag and kill whatever is flying it.

Some cancers have more macrophages than T cells. Some of these macrophages are counter-productive: not only do they not help, they may also secrete substances that put T cells to sleep and make the tumors grow more quickly.

Mast cells. These are immune cells involved in the allergic response. What do they have to do with prostate cancer? Apparently something, because PCF Young Investigator Karen Sfanos, Ph.D., at Johns Hopkins, and colleagues just discovered that men who have more mast cells are less likely to have a recurrence of prostate cancer after radical prostatectomy.

Dendritic cells: These are the cells that stand in the wings and give the T cells stage directions, pointing out which flags are “foreign,” or “dangerous” – similar to macrophages, but as even more professional T cell educators. They also supply a potent activation sauce that encourages the T cells that target foreign invaders to get out there and do their thing – multiply, attack, kill!

B cells. If T cells are the stars, B cells are the co-stars. They make Y-shaped antibodies, which grab onto the flags on a cancer cell. Antibodies attract the macrophages to come and gobble up anything they have picked out. B cells are like a Neighborhood Watch on steroids. Think of the nosy neighbor on “Bewitched,” Mrs. Gladys Kravitz, watching for suspicious activity through her binoculars, spying in the bushes, or peeping through the window. Now imagine Mrs. Kravitz on steroids – as a drone, maybe – flying around the body looking for anything that’s not supposed to be there. They don’t do the actual killing of the enemy cells, but they aim the laser at it so macrophages can gobble it up and educate T cells to see it.

“B cells are far less studied than T cells in cancer, but they’re incredibly promising,” notes Simons. “Prostate cancer generally shuts them down with checkpoints, too. But we think we have identified a checkpoint inhibitor for them, as well. It would be a very good thing to have prostate cancer cells making antibodies.” As a matter of fact, Drake’s team published a paper showing that if men taking Provenge make more and better antibodies, they seem to live longer.

Helper T cells. We weren’t going to talk about other T cells, but these cells help the B cells that make antibodies to do their jobs.